In our studies of the mood and behavioral effects of GnRH agonist-induced hypogonadism and hormone replacement, we have observed the development of clinically significant mood symptoms and loss of sexual interest in less than 10% and 30%, respectively, of healthy, young men and women in whom hypogonadism was induced by GnRH agonist (despite the presence of hot flushes experienced by 90 to 100% of these participants). The prediction of greater declines in sexual functioning during GnRH agonist-induced hypogonadism in both men and women was associated with baseline sexual functioning but not hormone levels. Specifically, those men and women with the highest levels of libido were at risk for experiencing the greatest loss of sexual functioning during hypogonadism and the greatest benefits of hormone therapy. Additionally, we observed that in men changes in cerebrospinal fluid levels of the neurosteroid metabolite of testosterone, andosterone, (but not testosterone), correlated with sexual functioning during both the hypogonadal state and testosterone replacement. Our efforts to examine possible changes in cognitive function associated with GnRH agonist-induced hypogonadism alone and hormone replacement have been negative, and we have been unable to confirm earlier studies that short-term changes in sex steroids significantly impact on cognitive test performance. Specifically, we have observed no differences in episodic memory, spatial memory (as measured by the virtual Morris Water Maze), or working memory functions. These neuropsychological test data are consistent with recent studies across the natural menopause, however, they are in contrast to the results of several studies in basic neuroscience, and those of smaller clinic-based samples of women in whom menopause was induced surgically. Our studies examining the effects of changes in sex steroids on the stress response and HPA axis function have previously demonstrated that progesterone, but not estrogen, induces an increased stress hormone response that may be relevant in both women with severe PMD and PPD. Additionally, we identified that the sex differences in stress responsivity, with males having a greater HPA axis response than females, is maintained in the absence of sex steroids and, therefore, reflects organizational changes in the stress axis rather than acute activational effects of the presence or absence of gonadal steroids.[unreadable] In our earlier studies of regional cerebral blood flow using PET, we reported for the first time in humans that induced hypogonadism was associated with the elimination of the normal pattern of cortical activation in the dorsolateral prefrontal cortex as well as the posterior inferior temporal cortices and the inferior parietal lobule; whereas both estradiol and progesterone replacement restored the normal pattern of cortical activation during a working memory task. Additionally, in a related project, we demonstrated changes in reward-related neurocircuitry across the normal menstrual cycle with increased activations during the expectancy of the reward during the follicular phase, when estradiol levels are high. We have pursued these findings with the GnRH agonist-induced hypogonadism and ovarian steroid replacement paradigm and have identified the following: 1) Increased resting regional cerebral blood flow (rCBF), in the left lateral orbitofrontal cortex, left dorsomedial prefrontal cortex, left posterior hippocampus, during hypogonadism; 2) Increased cognition-activated regional cerebral blood flow in the right precuneous during mental rotation after estradiol replacement compared with both hypogonadism and progesterone replacement; 3) Increased activation of several brain regions involved in the anticipation of rewards (e.g., orbitofrontal cortex and hippocampal gyrus)during estradiol replacement compared with progesterone replacement; 4) Increased activation of the ventral striatum and rostral anterior cingulate cortex during estradiol replacement compared with progesterone at the time of reward delivery. Indeed, no reward-related region was found to have greater activation during progesterone replacement conditions.[unreadable] In summary, our studies of experimentally-induced hypogonadism in men and women have revealed changes in several physiologic systems relevant to the regulation of mood and behavior (e.g., regional cerebral blood flow, HPA axis) and inform our investigations of reproductive endocrine-related mood disorders (i.e., PMD, PPD, and depression during the menopause transition). Additionally, these studies have allowed examinations in humans (in some cases for the first time) of the effects of individual gonadal steroids. Additionally, our examination of the effects of hypogonadism in younger women and men, who were not experiencing the potential CNS effects of reproductive aging, have allowed us to make inferences to be tested in future studies about the interactive effects of age and gonadal steroids on brain function. Nonetheless, the absence of uniform or pronounced alterations in mood or behavior (except sexual function) in asymptomatic volunteers during otherwise extreme manipulations of reproductive function emphasizes that alterations in gonadal steroids alone cannot explain the observed changes in mood and behavior in some men or women who experience depression during hormone transitions. Finally, ongoing studies within our group are now exploring the role of genomic variation in both the behavioral and physiologic responses to gonadal steroids using these same paradigms.